Cephalosporins are widely used and therapeutically important antibiotics. The compounds of Formula I are broad spectrum cephalosporin antibacterials and are, therefore, useful in the treatment of bacterial infections in animals. (U.S. Pat. No. 6,020,329, Col. 1, lines 13-14). In particular, Compound I is targeted for dogs and cats with indications for treatment of bacterial infections of the skin, soft tissue, periodontal and urinary tract.
Compound I, wherein M is Na+, and the preparation thereof, are disclosed in U.S. Pat. Nos. 6,001,997, 6,020,329 and 6,077,952. The text of the aforementioned patents and all other references cited in this specification are hereby incorporated by reference in their entirety.
Cephalosporin formulations are generally, however, unstable and a variety of different methods exist to increase stability including, inter alia, the adjustment of pH, crystallization, lyophilization, and the addition of stabilizers, such as sugars.
Cephalosporins may be somewhat stabilized within a certain pH range. The optimum pH range varies widely and is unpredictable for different classes of cephalosporins, requiring experimentation and stability tests. For example, Nassar et al., U.S. Pat. No. 5,401,842, disclosed formulations of crystalline cefepime salt buffered with trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methyl-glucamine and L(+) arginine to a pH of 3.5 to 7.0.
K. A. Conners et al. disclose that cephalothin has a broad stability range from a pH of between 2 to 8. Cepharadine, however, stabilizes at a more acidic pH between 1 to 5. Stability for Cefotaxime is achieved in the pH range of 3 to 7. (K. A. Connors, et al. Chemical Stability of Pharmaceuticals, John Wiley & Sons, New York, 1986, p305).
In some cases, cephalosporin formulations were stabilized by crystallization and lyophilization. For example, Gotschi, U.S. Pat. No. 5,138,066, describes formulations for parenteral administration as lyophilizates or dry powders for dilution with pharmaceutical carriers such as water or isotonic saline.
Bornstein et al, U.S. Pat. No. 4,002,748, disclose methods of preparing essentially amorphous cefazolin by utilizing certain lyophilization techniques, while Daugherty, EP 0327364, describes a lyophilization method to prepare formulations of a crystalline solvate of a 1-carbacephalosporin.
Some cephalosporins may be stabilized by addition of a variety of different sugars. Whether a certain sugar will stabilize a particular cephalosporin, however, is unpredictable. Furthermore, the ratio of sugar to cephalosporin to achieve optimum stability is also unpredictable. For example, Shamblin et al. disclose that the stability of amorphous cefoxitin sodium was improved by a factor of two when co-lyophilized with sucrose. The stability of cefoxitin was not affected, however, when co-lyophilized with trehalose. S. L. Shamblin, B. C. Hancock, M. J.Pikal, The Chemical Stability of Amorphous Cefoxitin Sodium in the Presence of Glassy Stabilizers, AAPS Pharm. Sci. Vol. I, Issue 4, 1999.
Similarly, Shima et al., EP 0134568B1, disclose that sugar (glucose, fructose or maltose) or an alkali metal salt of a mineral acid or carboxylic acid stabilized a specific lyophilized cephalosporin at a 0.01:1 to 0.5:1 weight ratio of stabilizer:cephalosporin. Mannitol, however, was not effective in stabilizing the disclosed cephalosporin compound.
Likewise, Almarsson et al., Tetrahedron 56 (2000) 6877-6885, disclose that sucrose improved chemical stability of a beta-lactam compound at a sucrose/drug ratio of 0.1:1 to 0.5:1.
Yoshioka, Y. et al., Pharm, Res. 17 (2000), 925-929, disclose the stability of cephalothin in the presence of dextran at a dextran/cephalothin ratio of 200:1.
Conversely, Hirai et al., U.S. Pat. No. 4,418,058, disclose that an excess amount, greater than 1:1, of a variety of different sugars or sugar alcohols adversely affected chemical stability of cephalosporins. Good stabilizing results were obtained, however, when the amount of added sugar or sugar alcohol was 0.1 to 1 sugar/cephalosporin.
Consequently, one of ordinary skill in the art cannot, in general, predict whether the addition of a particular sugar to any particular cephalosporin will achieve stability. Moreover, the optimum ratio of sugar:cephalosporin is also highly variable and unpredictable, absent experimentation. Furthermore, as discussed above, the optimum pH range of stability for a particular cephalosporin is also unpredictable.
A method of administration for Compound I is by parenteral administration. Other modes of administration include oral and topical. (U.S. Pat. No. 6,020,329, Col. 15, lines 1-2 Compound I is unstable, as both a solid and an aqueous solution. Furthermore, Compound I is hygroscopic. Consequently, a formulation and method for stabilizing Compound I would be a useful addition to the art.